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Table of Contents 

Contents 

I. INTRODUCTION .................................................................................................................. 3

A. Summary of Isoxaben Registration Review ......................................................................4

B. Public Comments ..............................................................................................................5

II. USE AND USAGE .............................................................................................................. 7

III. SCIENTIFIC ASSESSMENTS ........................................................................................... 7

A. Human Health Risk Assessment .............................................................................................7

1. Risk Conclusions .......................................................................................................... 8

2. Human Incidents........................................................................................................... 8

3. Tolerances ..................................................................................................................... 8

B. Ecological Risk Assessment ..................................................................................................8

1. Risk Conclusions .......................................................................................................... 9

2. Ecological Incidents ................................................................................................... 11

3. Characterization of Ecological Risk ........................................................................... 11

C. Benefits.................................................................................................................................12

D. Endangered Species Assessment ..........................................................................................13

E. Endocrine Disruptor Screening Program...............................................................................14

IV. INTERIM REGISTRATION REVIEW DECISION......................................................... 15

A. Risk Mitigation and Regulatory Rationale......................................................................15

1. Environmental Effects................................................................................................ 15

2. Herbicide Resistance .................................................................................................. 16

B. Tolerance Amendments ...................................................................................................16

C. Interim Registration Review Decision ............................................................................17

V. NEXT STEPS AND TIMELINE .......................................................................................... 17

A. Interim Registration Review Decision ............................................................................17

B. Implementation of Mitigation Measures .........................................................................17

Appendix A: Isoxaben Label Table ............................................................................................. 19
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I. INTRODUCTION

This document is the Environmental Protection Agency’s (EPA or the Agency) Interim 

Registration Review Decision for Isoxaben (case 7219, PC code 125851) and is being issued 

pursuant to 40 CFR sections 155.56 and 155.58. A registration review decision is the Agency's 

determination whether a pesticide meets, or does not meet, the standard for registration in the 

Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA). The Agency may issue, when it 

determines it to be appropriate, an Interim Registration Review Decision before completing a 

registration review. Among other things, the Interim Registration Review Decision may: 1)

require new risk mitigation measures; 2) impose interim risk mitigation measures; 3) identify 

additional data or other information required to complete the review; and 4) include schedules 

for submitting the required data, conducting the new risk assessment, and completing the 

registration review. For further information on isoxaben, additional documents can be found in 

EPA’s public docket (EPA-HQ-OPP-2007-1038) at www.regulations.gov. 

FIFRA, as amended by the Food Quality Protection Act (FQPA) of 1996, mandated the 

continuous review of existing pesticides. All pesticides distributed or sold in the United States 

generally must be registered by the EPA based on scientific data showing that they will not cause 

unreasonable risks to human health or to the environment when used as directed on product 

labeling. The registration review program is intended to make sure that, as the ability to assess 

and reduce risk evolves and as policies and practices change, all registered pesticides continue to 

meet the statutory standard of no unreasonable adverse effects. Changes in science, public 

policy, and pesticide use practices will occur over time. Through the registration review 

program, the Agency periodically re-evaluates pesticides to make sure that as these changes 

occur, products in the marketplace can continue to be used safely. Information on this program is 

provided as http://www2.epa.gov/pesticide-reevaluation. In 2006, the Agency implemented the 

registration review program pursuant to FIFRA section 3(g) and will review each registered 

pesticide every 15 years to determine whether it continues to meet the FIFRA standard for 

registration.

EPA is issuing an interim registration review decision for isoxaben so that it can (1) move 

forward with aspects of the registration review that are complete and (2) implement interim risk 

mitigation. The Agency is currently working with the U.S. Fish and Wildlife Service and the 

National Marine Fisheries Service to develop methodologies for conducting national endangered 

species assessments for pesticides. Therefore, although EPA has not yet fully evaluated risks to 

threatened and endangered species, the Agency will complete its endangered species assessment 

and any necessary consultation with the Services for isoxaben prior to completing the isoxaben

registration review. Likewise, the Agency will complete endocrine screening for isoxaben, 

pursuant to the Federal Food, Drug, and Cosmetic Act (FFDCA) section 408(p), before 

completing this registration review. Last, EPA will determine whether additional pollinator 

exposure and effects data are necessary to make a final registration review decision for isoxaben 

and issue a data call-in (DCI) to obtain any such data prior to completing the isoxaben 

registration review.

Isoxaben is a broad spectrum pre-emergent herbicide registered for use to control broadleaf 

weeds, grasses, and vines. The first product containing isoxaben was registered by EPA in 1989; 

therefore, isoxaben was not subject to EPA’s reregistration of older pesticides. Isoxaben is used 
4

around non-bearing food crops, ornamental trees, and shrubs in agriculture nurseries, rights-ofway, and urban areas. The first food uses of isoxaben on bearing nut trees and grape vineyards 

were registered in November 2010, and four pesticide tolerances were established for residues of 

isoxaben in or on almond hulls; grape; nut, tree, group 14; and pistachio.

This document is organized in five sections: the Introduction, which includes this summary and 

a summary of public comments and EPA’s response; Use and Usage, which describes how and 

why isoxaben is used and summarizes data on its use; Scientific Assessments, which summarizes 

EPA’s risk assessment, any revisions, and risk conclusions; Interim Registration Review 

Decision, which describes the mitigation measures to address risks of concern and the regulatory 

rationale for EPA’s registration review decision; and, last, the Next Steps and Timeline for 

completion of this registration review.

A. Summary of Isoxaben Registration Review 

Pursuant to 40 CFR section 155.50, EPA formally initiated registration review for isoxaben (case 

7219) in 2009. The following list highlights significant events that have occurred during the 

registration review of isoxaben. Documentation of these events for isoxaben can be found in 

EPA’s public docket, EPA-HQ-OPP-2007-1038, accessed at www.regulations.gov:

 December 19, 2007 – Publication of Isoxaben Preliminary Work Plan (PWP) for a 60-

day public comment period. The Preliminary Work Plan (PWP) was accompanied by the 

scoping document and problem formulation.

 June 13, 2008 – Final Work Plan (FWP) for Isoxaben was issued. Public comments were 

received from two sources during the 60-day comment period for the isoxaben PWP;

however, these comments did not change the risk assessment or data needs identified in 

the PWP. Therefore, the FWP did not modify the PWP.

 February 18, 2010 – Generic Data Call-In Notice (GDCI) for isoxaben was issued. 

 April 7, 2011 – Second GDCI issued for environmental fate and effects data needs 

identified during EPA’s review of a petition for the first isoxaben food use. 

 June 17, 2011 – Amended Final Work Plan for Isoxaben was issued to reflect the

additional environmental fate and effects data requirements and a revised registration 

review schedule for isoxaben. The registration review timeline for isoxaben was 

extended two years to allow for generation of additional data.

 September 24, 2014 – EPA published the preliminary risk assessments for isoxaben for a 

60-day public comment period: Preliminary Ecological Risk Assessment for the 

Registration Review of Isoxaben and Isoxaben – Preliminary Human Health Risk 

Assessment for Registration Review. EPA received comments from the Center for 

Biological Diversity (CBD) and Dow AgroSciences (Dow), one of two isoxaben 

technical registrants. These comments did not change the risk assessment conclusions. 
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For further information see the Isoxaben Proposed Interim Registration Review Decision, 

June 23, 2015.

 June 2015 – The Agency published the Isoxaben Proposed Interim Registration Review 

Decision, June 23, 2015,Response to Comments on the Isoxaben Registration Review 

Preliminary Risk Assessment, February 3, 2015, Non-Agricultural Use and Usage Report 

for the Herbicide Isoxaben in Support of Risk Mitigation & Preliminary Interim 

Decision, May 21, 2015, and the Isoxaben Qualitative Benefits Assessment, June 18, 

2015, in the registration review docket (EPA-HQ-OPP-2007-1038) for a 60-day public 

comment period. One comment was received from the Center for Biological Diversity 

(CBD), which is addressed below. 

 December 2015 – The Agency is now publishing the Isoxaben Interim Registration 

Review Decision. 

B. Public Comments

During the 60-day public comment period on the Isoxaben Proposed Interim Decision, which 

opened on August 11, 2015 and closed on October 9, 2015, the Agency received one comment, 

from the Center for Biological Diversity, an environmental and public interest group. The public 

comments, and EPA’s response, are summarized below. Public comments in their entirety are 

located in the docket, EPA-HQ-OPP-2007-1038

COMMENTS RECEIVED FROM CBD (EPA-HQ-OPP-2007-1038-0037)

Comment: CBD opposes the proposed reregistration of isoxaben at this time as premature 

because they assert that the Agency has determined that isoxaben has the potential to cause 

adverse effects to species. In CBD’s comments on the Proposed Interim Registration Review 

Decision for Isoxaben, they focus on EPA’s duty to initiate consultation with the U.S. Fish and 

Wildlife Service and the National Marine Fisheries Service (the Services) prior to completion of 

the registration review process for isoxaben. CBD states that the reregistration of isoxaben

cannot be completed in compliance with EPA’s obligations under both FIFRA and the ESA until 

the EPA concludes that the continued use of isoxaben will have “no effect” on listed species or 

critical habitat or completes consultation. CBD also contends that there are readily available 

data and information sources that would allow EPA to complete Step 1 of the Interim 

Approaches for National Level Endangered Species Assessments Based on the Recommendations 

of the National Academy of Science. CBD refers to their previous comments1 on EPA’s draft 

ecological risk assessment, which provided specific label language to implement the Bulletins 

Live! System, stating that this label language would enable EPA to comply with current and 

continuing ESA duties. (CBD incorporated these and all other previous comments on the draft 

ecological risk assessment by reference.) Last, they state that EPA must take a precautionary 

approach and enter into consultations with the Services on isoxaben as outlined in the Interim 

Approaches document. 

 

1 EPA-HQ-OPP-2007-1038-0028
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Response: As an initial matter, CBD’s comments suggest that it may not fully appreciate the 

distinction between EPA’s interim and final registration review decision. Additionally, CBD 

seems to use “reregistration” interchangeably with “registration review.” Both are separate 

programs mandated by FIFRA; isoxaben is currently undergoing Registration Review. As 

provided in EPA’s registration review regulations at 40 CFR section 155.56, EPA may, in its 

discretion, issue an interim decision before the completion of registration review when, among 

other things, it determines that it cannot complete registration review because additional 

information is necessary to complete the Agency’s assessment. In addition, section 155.56 also 

provides that EPA may require risk mitigation measures in an interim decision. Consistent with 

this provision, EPA is issuing this interim registration review decision for isoxaben in part so that 

it can move forward with aspects of the registration review decision that are complete while EPA 

continues to work with the Services on developing the interim approaches that will be used to 

complete its registration review endangered species assessment for isoxaben. Under section 

3(g) of FIFRA, EPA must complete the registration review of isoxaben by October 1, 2022. 

While EPA could, therefore, choose not to complete any aspect of the isoxaben registration 

review for several more years until it completes its endangered species assessment and any 

necessary consultation, EPA believes the public and the environment benefit from EPA’s early 

action on the matters covered by this interim decision including risk mitigation, such as use of 

spray nozzles limiting isoxaben droplet size, a spray minimum release height, boom or nozzle 

shielding, and restricting application to only when wind speed is between 2 and 10 mph-- as 

described in Section IV of this document. EPA does not believe the Endangered Species Act 

compels a contrary result. Taking early action to address some risks now serves to benefit the 

environment and does not preclude EPA from taking any additional necessary actions to address 

effects to listed species that EPA concludes are necessary as it works to complete registration 

review.

Accordingly, EPA’s previous response to CBD’s comments on the draft ecological risk 

assessment (in the Proposed Interim Decision) stated that EPA plans to address CBD’s concerns 

with the development of its Final Registration Review Decision. This is still EPA’s plan. EPA 

anticipates initiating consultation with the Services after issuing the Interim Registration Review 

Decision, but prior to issuing the Final Registration Review Decision. The Agency’s Interim 

Registration Review Decision, like the Proposed Interim Decision, states that EPA is not making 

a complete endangered species finding, and that EPA’s Final Registration Review Decision for 

isoxaben will depend upon the result of an ESA Section 7 consultation with the Services, an 

assessment of non-target exposure to bees, as well as the FFDCA section 408(p) endocrine 

screening requirements.

EPA is still in the process of developing the interim approaches based on the 2013 NAS Report 

recommendations, including Steps 1 and 2 of the Biological Evaluation for listed species. 

CBD’s previous comments provide reference to the available critical habitat; however, as CBD 

noted, not all species have critical habitat. Furthermore, critical habitat is just one piece of the 

species’ range. EPA is working with the Services to obtain the best available species range 

information for all listed species. We are also working together to determine the appropriate 

pesticide use footprint. EPA will be taking public comment on our interim approaches as 

developed and implemented for the three pilot chemicals: chlorpyrifos, diazinon and malathion. 

As a result, EPA may develop a revised approach for Steps 1 and 2 through work on the three 

pilot chemicals before completing Step 1 for isoxaben. 
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CBD’s previous comments also provided label language referring pesticide applicators to EPA’s 

Bulletins Live! System, and a statement that all product labels for isoxaben must contain this 

language. However, since there are no Bulletins for isoxaben in Bulletins Live! Two, it is 

unnecessary, at this point in time, to include this language on the label for isoxaben. Inclusion of 

a reference to Bulletins on the product label when no Bulletins exist is likely to result in 

confusion for pesticide applicators and growers. However, EPA is in agreement with CBD that 

Bulletins are the appropriate mechanism to implement any necessary geographically-specific 

pesticide use limitations intended to protect listed species. EPA plans to use Bulletins Live! Two

to implement any Bulletins that would be generated as we complete the evaluation of potential 

risks of isoxaben to listed species and designated critical habitat.

II. USE AND USAGE

Isoxaben is a pre-emergent benzamide herbicide registered for use to control broadleaf weeds, 

grasses and vines. It is classified by the Weed Science Society of America (WSSA) as a Group 

21 herbicide that inhibits cell wall biosynthesis. Isoxaben is registered for the following nonagricultural uses: turfgrass, ornamentals (landscape, container and field), 

groundcovers/perennials, conifer plantations/hardwood nurseries, non-bearing fruit and nut trees, 

non-bearing vineyards, and other non-cropland. It is also registered for agricultural use on 

bearing fruit and nut trees and vineyards. Much of the orchard and vineyard use is in California. 

The majority of uses have a maximum application rate of 1.0 lb ai/A/application, three 

applications per year, with a 60-day re-application interval. Isoxaben products are generally 

registered for both non-residential and residential uses. In terms of percent crop treated, greatest 

use was on grapes (2.5-5% crop treated), followed by pistachios (≤2.5%)2. Aerial applications of 

isoxaben are not permitted. 

For additional details on isoxaben use and usage see the January 28, 2014 Isoxaben Screening 

Level Usage Analysis, and the May 21, 2015 Non-Agricultural Use and Usage Report for the 

Herbicide Isoxaben (PC Code #125851) in Support of Risk Mitigation & Preliminary Interim

Decision.

 

III. SCIENTIFIC ASSESSMENTS

A. Human Health Risk Assessment

A summary of the Agency’s human health risk assessment is presented below. The Agency used 

the most updated Agency science policies and risk assessment methodologies to prepare a 

quantitative risk assessment in support of the isoxaben registration review. For a detailed 

discussion of the human health assessment for isoxaben, see Isoxaben – Preliminary Human 

Health Risk Assessment for Registration Review, dated September 11, 2014, available in the 

public docket EPA-HQ-OPP-2007-1038, at: http://www.regulations.gov/.

 

2 2011-2013 usage data. 
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1. Risk Conclusions

EPA has no human health risks exceeding the Agency’s level of concern for isoxaben. There are 

no dietary (food and drinking water), residential handler, residential post-application, aggregate

(combined food, drinking water, residential/bystander), or occupational risks exceeding the 

Agency’s level of concern for all registered uses of isoxaben. No dermal endpoint was identified, 

therefore exposure assessments were not required for this exposure scenario. 

In addition, isoxaben does not appear to share a common mechanism of toxicity with other 

substances and does not appear to produce any toxic metabolite or degradates also produced by 

other substances. Therefore, EPA has not made a common mechanism of toxicity finding for 

isoxaben and any other substance. For more information on EPA’s efforts to determine which 

pesticides share a common mechanism of toxicity and to evaluate cumulative effects, see 

http://www2.epa.gov/pesticide-science-and-assessing-pesticide-risks/cumulative-assessmentrisk-pesticides. 

2. Human Incidents

EPA consulted the Office of Pesticide Programs Incident Data System (IDS), the National

Institute of Occupational Safety and Health Sentinel Event Notification System for Occupational 

Risks (SENSOR/NIOSH) database, and the National Poison Center System (NPCS) database for 

potential human poisonings related to isoxaben. IDS reported one case related to exposure to 

isoxaben. From 1998 to 2003, there were no cases of human poisoning reported for isoxaben in 

the SENSOR/NIOSH database. From 1993 through 2005 there were sixteen exposures to 

isoxaben in the NPCS. At this time, there is no evidence suggesting a plausible association 

between exposure to isoxaben and a moderate or severe health outcome. Therefore, the Agency 

believes that no further investigation of human incidents is warranted at this time. However, if 

additional information comes in, the Agency will further examine. 

3. Tolerances

Although EPA has determined that there are no adverse human health effects from use of 

isoxaben, the Agency will pursue changes to the tolerance for isoxaben to update the crop group 

tolerances for tree nuts. Specific changes are described in the September 11, 2014 document,

Isoxaben: Preliminary Human Health Risk Assessment for Registration Review, and in Section 

IV, A. of this document. The Agency is not aware of any international harmonization issue 

related to the existing isoxaben tolerances.

B. Ecological Risk Assessment 

A summary of the Agency’s ecological risk assessment is presented below. The Agency used 

the most up-to-date Agency science policies and risk assessment methodologies to prepare a 

quantitative ecological risk assessment in support of the registration review of isoxaben. For a 

detailed discussion of the ecological assessment for isoxaben, see the following documents, 

available in the public docket EPA-HQ-OPP-2007-1038, at: http://www.regulations.gov/ 
9

 Preliminary Ecological Fate and Ecological Risk Assessment in Support of the 

Registration Review of Isoxaben, September 3, 2014, and

 Response to Comments on the Isoxaben Registration Review Preliminary Risk 

Assessment, February 3, 2015.

EPA is currently working with its federal partners and other stakeholders to implement an 

interim approach for assessing potential risk to listed species and their designated critical 

habitats. Once the scientific methods necessary to complete risk assessments for listed species 

and their designated critical habitats are finalized, the Agency will complete its endangered 

species assessment for isoxaben. As such, potential risks to listed species will not be discussed 

further in this document. EPA’s risk concerns for nonlisted, nontarget species only are described 

further below. 

1. Risk Conclusions

The Agency completed its preliminary ecological risk assessment for isoxaben in September 

2014. This assessment showed that isoxaben is not expected to cause adverse effects to 

freshwater or estuarine/marine organisms. Acute and chronic risk quotients (RQs) for fish, 

aquatic invertebrates, and aquatic nonvascular plants (algae) are below EPA’s level of concern.3

In addition, acute and chronic risk estimates for birds, reptiles, and amphibians are below EPA’s 

level of concern. Therefore, EPA does not have acute or chronic risk concerns for these taxa. 

The Agency does not anticipate acute risks to mammals, but some chronic RQs for mammals 

exceed the level of concern. These RQs are ≤3.84. 

The preliminary ecological risk assessment showed potential risks of concern to terrestrial and 

aquatic vascular plants. RQs for terrestrial plants range from 1-12; RQs for aquatic plants range 

from 1-9. EPA also has potential chronic risk concerns to non-listed mammals (RQs range from 

1-4). The risk concerns for nontarget species will be described further below. 

When initially scoping the registration review for isoxaben, EPA did not identify the need for 

any additional studies to evaluate potential effects on pollinators. However, since the issuance of 

the June 2014 Guidance for Assessing Pesticide Risks to Bees4, EPA has begun to require these 

data where applicable. EPA is currently determining whether additional pollinator data are 

needed for active ingredients in registration review whose dockets opened prior to June 2014. 

For those active ingredients where EPA determines that additional pollinator exposure and 

effects data are necessary to help make a final registration review decision, EPA intends to issue 

a DCI to obtain these data. In the near future, EPA will provide further information and 

guidance on this effort. For isoxaben, the pollinator studies that could be required are included in 

Table 1 below. The Agency will require data it believes are needed to help inform the pollinator 

risk assessment.

 

3 For non-listed species, the Level of Concern (LOC) is 1; RQs > 1 exceed the LOC. 

4 http://www2.epa.gov/sites/production/files/2014-6/documents/pollinator_risk_assessment_guidance_06_19_14.pdf
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Table 1. Potential Pollinator Data Requirements

Guideline # Study

850.3020*† Acute contact toxicity study with adult honey bees

850.3030*† Honey bee toxicity of residues on foliage

850.3040** Field testing for pollinators

Non-Guideline*†(OECD 213) Honey bee adult acute oral toxicity

Non-Guideline* (OECD 237) Honey bee larvae acute oral toxicity

Non-Guideline* Honey bee adult chronic oral toxicity

Non-Guideline* Honey bee larvae chronic oral toxicity

Non-Guideline** Residues in pollen and nectar/field residue analysis

Non-Guideline** (OECD 75) Semi-field testing for pollinators (tunnel or colony feeding studies)

*Tier 1 Laboratory-based studies. **Tier 2 and 3 (Semi-field and full field colony-level studies). The need for a 

higher tier test for pollinators will be determined based upon lower-tiered tests and/or other lines of data and the 

need for a refined pollinator risk assessment. † Acceptable data have already been submitted for isoxaben or the 

study is waived based on available data.

Terrestrial and Aquatic Vascular Plants. In the preliminary risk assessment for isoxaben, the 

Agency used the TerrPlant model to calculate RQs for nontarget terrestrial and semiaquatic

plants exposed to isoxaben from spray drift alone and for spray drift and runoff combined, in 

both dry upland and semi-aquatic wetland habitats. The preliminary risk assessment showed 

potential risk concerns for nontarget terrestrial plants (RQs ≤12) and for nontarget aquatic 

vascular plants (RQs ≤8.2). The RQs for terrestrial plants were based on isoxaben parent only;

however, the RQs for aquatic plants were based on estimated environmental concentrations 

(EECs) for isoxaben and its degradates5(total toxic residues, TTR) using the conservative 

assumption that the degradates are as toxic as isoxaben, the parent compound. RQs calculated 

using the EEC for isoxaben alone also exceeded the LOC (RQs ≤3.2). 

EPA examined the effect of spray drift to nontarget plants using the AgDrift model. Ground 

application at the maximum single application rate, 1.0 lbs ai/A, was modeled for all of the 

species tested in the seedling emergence and vegetative vigor studies. Lettuce was the most 

sensitive species tested. An effects distance is the estimated distance (feet) from the edge of the 

treated field where an herbicide has the potential to adversely effect nontarget plants due to spray 

drift. The effects distance for seedling emergence for lettuce, the most sensitive species, was 249 

feet from the edge of the field. The effects distance for vegetative vigor for ryegrass, the most 

sensitive plant species, was 174 feet from the edge of field. 

Mammals. In the preliminary risk assessment for isoxaben, the Agency estimated potential 

chronic risks to mammals. Because the available acute toxicity data for isoxaben showed no 

mortality, and no sublethal effects were observed in any of the mammalian studies at the highest 

levels tested, acute RQs were not calculated. Only nondefinitive acute and subacute toxicity 

endpoints were available for mammals; therefore, acute RQs were not calculated. EPA does not 

anticipate acute risks of concern for mammals. 

 

5 The isoxaben degradates identified in an aqueous photolysis study were considered in the preliminary risk 

assessment. 
11

EPA estimated chronic RQs for isoxaben using both a dietary and dose basis. Chronic RQs did 

not exceed the LOC for mammals when exposure was calculated on a dietary basis for mammals. 

However, there were limited RQ exceedances on a dose basis for all registered uses; dose-based 

RQs ranged from <1 to 3.84. The Agency used an endpoint of reduced parental body weight 

from a rat reproductive toxicity study to evaluate chronic risk to mammals. The study No 

Observed Adverse Effect Level (NOAEL) was 40 mg/kg body weight; the Lowest Observed 

Adverse Effect Level (LOAEL) was 200 mg/kg body weight. Chronic mammalian RQs were 

calculated using the NOAEL of 40 mg/kg, high end residue values from the Kenega nomogram, 

and the maximum label application rate and number of applications per year for isoxaben. 

2. Ecological Incidents

Between 1994 and 2010, EPA received reports of six incidents involving plants associated with 

herbicide products containing isoxaben. No incident reports have been received since 2010. 

Most of these incidents were the result of legal registered use of herbicides containing isoxaben, 

but there was one incident of misuse. When the number of affected plants was reported, between 

35,000 and 676,000 individual nursery or ornamental plants were affected, including woody 

plants. EPA has not received any incident reports for isoxaben since 2010, but this lack of 

reporting does not necessarily indicate a lack of incidents. For a detailed discussion of the 

ecological incidents for isoxaben, see Preliminary Ecological Fate and Ecological Risk 

Assessment in Support of the Registration Review of Isoxaben, dated September 3, 2014.

3. Characterization of Ecological Risk

The preliminary risk assessment for isoxaben identified some RQs that exceeded EPA’s level of 

concern (LOC) for nontarget species. Although the Agency uses the LOC as an indicator of 

potential adverse effects to nontarget organisms, LOC exceedances are only one line of evidence 

used by EPA to describe the risks posed by a pesticide to nontarget organisms. This risk 

characterization section describes other lines of evidence for isoxaben, puts the LOC 

exceedances into a broader context, and provides additional perspective on the exceedences. 

Aquatic Vascular Plants. The preliminary risk assessment for isoxaben identified potential risk 

concerns for aquatic vascular plants from potential runoff; RQs were ≤8.2 for TTR (isoxaben 

parent and degradates) and ≤3.2 for isoxaben parent only. The isoxaben degradates considered 

in the risk assessment were based on aquatic photolysis data. Thus, the TTR RQs might be more 

relevant for shallow or clear water bodies where photolysis of isoxaben is more likely to occur. 

Furthermore, by using the TTR approach, EPA assumed that the isoxaben degradates had 

equivalent toxicity to the parent. Therefore, the TTR RQs might overestimate the risk to aquatic 

vascular plants. 

Terrestrial Plants. The preliminary risk assessment for isoxaben indicated potential risk to 

nontarget terrestrial plants; RQs for plants were ≤11.8 (ground spray application, 1 lb ai/A, 

single application). Although runoff is a major factor in nontarget terrestrial plant exceedances, 

it is difficult to estimate how far from the application site adverse effects may occur as a result of 

runoff. However, the Agency was able to estimate spray drift effects distances for isoxaben to be 

249 feet from the edge of the field for seedling emergence (lettuce) and 174 feet from the edge of 

field for vegetative vigor (ryegrass). The effects distance is the off-field area of potential adverse 
12

effects to nontarget plants. Beyond this distance, there would be low potential for adverse effects 

to nontarget plants. These effects distance estimates were derived using from AgDrift model 

default values, including a 50 inch release height (high boom for ground application) and an 

ASABE6 droplet size spectrum of “very fine to fine.” These model defaults were used because 

not all of the current isoxaben product labels specify droplet size distributions, boom heights, or 

other drift reduction measures that would reduce the effects distance for isoxaben. For example, 

using a low boom (20 inch release height) and spray nozzles producing an ASABE droplet size 

spectrum of “fine to medium/ coarse” spray droplets would reduce the effects distance for 

lettuce from 249 to 36 feet from edge of field. To address concerns for spray drift, EPA is 

requiring0 label amendments to reduce drift. By reducing spray drift, these label amendments 

will reduce the likelihood of exposure and risk to nontarget plants and animals. The technical

registrants for isoxaben (Dow and Celsius) have agreed to these drift reduction measures.

Terrestrial Mammals. The preliminary risk assessment for isoxaben showed chronic dose-based 

RQs ≤3.84, exceeding the target LOC of 1 for mammals; however, dietary-based RQs did not 

exceed the LOC. Nonetheless, EPA does not expect chronic risk to mammals because the 

assessment is based on a number of conservative assumptions. The only endpoint available to 

evaluate chronic risk to mammals was for reduced parental weight gain from a rat reproductive 

toxicity study. No other adverse effects were seen in the study. Furthermore, no effects on 

developmental or maternal toxicity were observed at doses up to 1000 mg/kg/day in prenatal 

developmental studies on isoxaben in the rat and rabbit. In addition, the RQ values also assume 

that the mammalian diet consists of a single food item, all of which is treated with isoxaben at 

the maximum label application rate and number of applications; these are conservative 

assumptions. 

C. Benefits

In support of registration review, a qualitative assessment of the benefits of isoxaben was 

conducted. The largest use of isoxaben is to manage pre-emergent broadleaf weeds in ornamental 

nurseries and on golf course turf. There is also some use for managing pre-emergent broadleaf 

weeds in bearing and non-bearing fruit and nut orchards and vineyards. Isoxaben is an effective 

broad spectrum herbicide for target weeds. For additional details on the benefits of isoxaben see 

the June 18, 2015 memo, Isoxaben Qualitative Benefits Assessment and the May 21, 2015 memo, 

Non-Agricultural Use & Usage Report for the Herbicide Isoxaben in Support of Risk Mitigation 

& Preliminary Interim Decision.

Isoxaben is the only benzamide chemical (WSSA Group 21)7that inhibits cell wall biosynthesis. 

While there are some other cell wall biosynthesis inhibitor herbicides (WSAA Groups 20, 28, 

29), isoxaben is the only biosynthesis inhibitor herbicide of the benzamide chemistry. Therefore, 

isoxaben provides a unique chemistry as a pre-emergence herbicide where there are limited 

modes of action available for controlling more problematic weeds. Cooperative extension 

 

6 ASABE is the American Society of Agricultural and Biological Engineers. 

7 Weed Science Society of America. 2014. Herbicide Handbook, 10th Edition. Dale L. Shaner Ed. Herbicide 

Handbook Committee. 
13

specialists report that isoxaben is among the most effective herbicides for difficult to control 

weeds in nurseries, turf, and orchards/vineyards.

Boom height and droplet size are key factors to reduce the potential for drift to non-target plants. 

Although the Agency does not have information specific to isoxaben applications regarding 

droplet size or boom height, it appears to be a chemical that is amenable to application with 

course droplet and low boom height. This is supported by its low volatility and presumed 

efficacy when applied at low boom height and coarse droplet size.

Turf. On turf, isoxaben is registered for use for pre-emergence control of a number of difficult to 

control annuals and perennial weeds. The unique mode of action and effectiveness of isoxaben

may provide a particular benefit for the user in a weed control program.

Nurseries. Benefits of isoxaben nursery use are its effectiveness against difficult-to-control 

weeds and long-term weed control. For production of container-grown ornamentals, isoxaben 

has been recommended for control of bittercress, common groundsel, creeping woodsorrel, 

pearlwort, and spurge. It is considered an excellent herbicide for broadleaf weed control; some 

weeds may be controlled for up to 18 months. 

Orchards and Vineyards. For orchards and vineyards, isoxaben is particularly effective for

managing weeds such as fleabane that have been difficult to control with other herbicide 

chemistries. When applied in the fall or winter, isoxaben can provide 4-5 months of weed 

control. Because isoxaben has a unique mode of action, it is a good rotational herbicide with 

other herbicide modes of action to manage weed resistance, and it targets a wide range of weed 

pests. Limited pre-emergence chemistries are available for orchards and vineyards. Weeds such 

as hairy fleabane, common mallow and marestail are important orchard weeds effectively 

managed by isoxaben. Integrated weed management programs that include pre-emergence 

herbicides can be effective for orchard and vineyard cropping systems. 

 D. Endangered Species Assessment

In November 2013, the EPA, along with the Services and the USDA, released a summary of 

their joint Interim Approaches for assessing risks to endangered and threatened (listed) species 

from pesticides. The Interim Approaches were developed jointly by the agencies in response to 

the National Academy of Sciences’ (NAS) recommendations and reflect a common approach to 

risk assessment shared by the agencies as a way of addressing scientific differences between the 

EPA and the Services. The NAS report8 outlines recommendations on specific scientific and 

technical issues related to the development of pesticide risk assessments that EPA and the 

Services must conduct in connection with their obligations under the ESA and FIFRA. 

The joint Interim Approaches were released prior to a stakeholder workshop held on November 

15, 2013. In addition, the EPA presented the joint Interim Approaches at the December 2013 

Pesticide Program Dialogue Committee (PPDC) and State-FIFRA Issues Research and 

 

8 Assessing Risks to Endangered and Threatened Species from Pesticides. Available at 

http://www.nap.edu/catalog.php?record_id=18344
14

Evaluation Group (SFIREG) meetings. The agencies also held stakeholder workshops —in April 

and October 2014, and in April 2015 — allowing additional opportunities for stakeholders to 

comment on the Interim Approaches. Additional workshops are planned to enhance stakeholder 

involvement. As part of a phased, iterative process for developing the Interim Approaches, the 

agencies will also consider public comments on the Interim Approaches in connection with the 

development of upcoming Registration Review decisions. The details of the joint Interim 

Approaches are contained in the white paper Interim Approaches for National-Level Pesticide 

Endangered Species Act (ESA) Assessments Based on the Recommendations of the National 

Academy of Sciences April 2013 Report9, dated November 1, 2013.

Given that the agencies are continuing to develop and work toward implementation of the 

Interim Approaches to assess the potential risks of pesticides to listed species and their 

designated critical habitat, the ecological risk assessment supporting this Interim Decision for 

isoxaben does not contain a complete ESA analysis that includes effects determinations for 

specific listed species or designated critical habitat. Although EPA has not yet completed effects 

determinations for specific species or habitats, for this preliminary assessment EPA’s evaluation 

assumed, for all taxa of non-target wildlife and plants, that listed species and designated critical 

habitats may be present in the vicinity of the application of isoxaben. This assessment will allow 

EPA to focus its future evaluations on the types of species where the potential for effects exists 

once the scientific methods being developed by the agencies have been fully vetted. Once the 

agencies have fully developed and implemented the scientific methodology for evaluating risks 

for listed species and their designated critical habitats, these methods will be applied to 

subsequent analyses for isoxaben as part of completing this registration review.

E. Endocrine Disruptor Screening Program

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse 

outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and 

chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, 

reproductive, and general or systemic toxicity. These studies include endpoints which may be 

susceptible to endocrine influence, including effects on endocrine target organ histopathology, 

organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, 

and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and 

chronic studies that assess growth, developmental and reproductive effects in different 

taxonomic groups. As part of its most recent registration decision for isoxaben, EPA reviewed 

these data and selected the most sensitive endpoints for relevant risk assessment scenarios from 

the existing hazard database. However, as required by FFDCA section 408(p), isoxaben is

subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP). 

EPA has developed the EDSP to determine whether certain substances (including pesticide 

active and other ingredients) may have an effect in humans or wildlife similar to an effect 

produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator 

may designate.” The EDSP employs a two-tiered approach to making the statutorily required 

 

9 Available at http://www2.epa.gov/endangered-species/assessing-pesticides-under-endangered-species-act#report
15

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a 

chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal 

systems. Chemicals that go through Tier 1 screening and are found to have the potential to 

interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA 

will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 

testing is designed to identify any adverse endocrine-related effects caused by the substance, and 

establish a dose-response relationship between the dose and the E, A, or T effect. 

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between 

October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 

chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. A second list of 

chemicals identified for EDSP screening was published on June 14, 201310 and includes some 

pesticides scheduled for Registration Review and chemicals found in water. Neither of these 

lists should be construed as a list of known or likely endocrine disruptors. For further 

information on the status of the EDSP, the policies and procedures, the lists of chemicals, future 

lists, the test guidelines and the Tier 1 screening battery, please visit EPA’s EDSP website.11 

In this interim decision, EPA is making no human health or environmental safety findings 

associated with the EDSP screening of isoxaben. Before completing this Registration Review, 

the Agency will make an EDSP FFDCA section 408(p) determination.

IV. INTERIM REGISTRATION REVIEW DECISION

A. Risk Mitigation and Regulatory Rationale

1. Environmental Effects

As discussed in the Ecological Risk Assessment section of this document, isoxaben has been 

determined to pose a potential risk concern for nontarget terrestrial plants and aquatic vascular 

plants. In addition, there is a lack of consistency across isoxaben product labels regarding label 

language to reduce potential off-target spray drift. To address these concerns, the isoxaben 

product labels must be amended (see Appendix A) to reduce spray drift. EPA’s intention is to 

establish a baseline level of protection against spray drift that is consistent across all isoxaben 

products registered for use in agricultural settings. By reducing spray drift, these label 

amendments will reduce the likelihood of exposure and risk to nontarget plants and animals. 

Both isoxaben technical registrants (Dow Chemical and Celsius) have agreed to the following 

label amendments: 

 Use of spray nozzles limiting product droplet size during applications to medium or coarse in 

accordance with the American Society of Agricultural and Biological Engineering (ASABE) 

standard S-572;

 

10 See http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPPT-2009-0477-0074 for the final second list of 

chemicals.

11 http://www2.epa.gov/endocrine-disruption
16

 Spray boom applications at the lowest height that safely permits uniform coverage of the soil 

and minimizes droplet evaporation;

 Boom or nozzle shielding to reduce the effects of wind or air current on drift; and

 Spray application is allowed only when wind speed is between 2 and 10 mph.

2. Herbicide Resistance 

To prevent the development of resistance to isoxaben among common weeds, product labels 

must be amended for all isoxaben herbicide products (except for those registered solely for 

homeowner use) to contain resistance-management labeling. These label requirements follow the 

recommendations of the Weed Science Society of America publication, Reducing the Risks of 

Herbicide Resistance, Best Management Practices and Recommendations12. The Agency first 

provided guidance on resistance management labeling in Pesticide Registration (PR) Notice 

2001-5, Guidance for Pesticide Registrants on Resistance Management Labeling. EPA is

requiring the following herbicide-resistance labeling for isoxaben: 

 Mandatory listing of herbicide mechanism of action, and/or Weed Science Society of 

America herbicide group number, at the top of the first page of each product label; 

 Instructions to alternate use of products containing isoxaben with other herbicides with 

different mechanisms of action;

 Instructions to use the highest practical finished spray volume; 

 Recommendations to scout for weeds before and after isoxaben application, to ensure 

proper identification of weeds and growth stage and to confirm product performance; 

 Instructions to report herbicide failure to local extensions specialists, certified crop 

advisors, and/or isoxaben registrants; and 

 Instructions to clean application equipment between sites, and to avoid moving plant 

material between sites. 

EPA believes that the inclusion of herbicide-resistance management language on isoxaben labels 

is important to slow the development of resistance to this herbicide while maintaining flexibility 

for growers. Weed resistance is a complex issue and registrants play an important role in 

ensuring effective resistance management. Educating all stakeholders about managing herbicide

resistance is important, and the product label is a critical part of this effort.

3. Tolerance Amendments

Although EPA has determined that there are no adverse human health effects from use of 

isoxaben, the Agency will pursue changes to the tolerances for isoxaben to correct commodity 

 

12 Norsworthy et al. 2012. Weed Science 2012. Special Issue: 31-62. 
17

definitions, update crop tolerances, and correct tolerances values for indirect or inadvertent

residues. 

EPA will pursue the following changes to the isoxaben tolerance listed in 40 CFR § 180.650:

 The tolerance for “Nut, tree, group 14” will be updated to “Nut, tree, group 14-12.” The 

tolerance level remains unchanged at 0.02 ppm. 

 The tolerance for “Pistachio” will be revoked concomitant with the revision of the 

tolerance for tree nuts to include pistachio. 

 The tolerances for indirect or inadvertent residues of isoxaben established in 40 CFR 

§ 180.650(d) will be corrected to three significant figures, in accordance with current

policy. 

EPA will conduct rulemaking to implement these tolerance changes, in accordance with FFDCA. 

B. Interim Registration Review Decision

In accordance with 40 CFR Sections 155.56 and 155.58, the Agency is issuing this Interim 

Registration Review Decision. Except for the EDSP, pollinator, and ESA components of this 

case, the Agency has made the following Interim Registration Review Decision: (1) with the 

possible exception of pollinator studies listed in Section IIIB1 of this document, no additional 

data are required at this time; and (2) changes to the affected registrations and their labeling are 

necessary at this time.

In this interim registration review decision, EPA is making no human health or environmental 

safety findings associated with the EDSP screening of isoxaben, nor is it making a complete 

endangered species finding. The Agency’s final registration review decision for isoxaben will 

depend upon the result of an ESA Section 7 consultation with the Services, an EDSP FFDCA 

section 408(p) determination, and an assessment of non-target exposure to bees.

V. NEXT STEPS AND TIMELINE

A. Interim Registration Review Decision

In accordance with 40 CFR Sections 155.56 and 155.58, the Agency is issuing this Interim 

Registration Review Decision, and placing it in the isoxaben registration review docket (EPAHQ-OPP-2007-1038). The Agency’s final decision on the isoxaben registration review case will 

depend upon the results of the EDSP determination, an ESA consultation with the Services, and 

an assessment of non-target exposure to bees. 

B. Implementation of Mitigation Measures
18

Registrants must submit amended labels, which implement the label changes summarized in 

Appendix A, to EPA within 60 days of issuance of the Interim Registration Review Decision for 

isoxaben. 
19

Appendix A: Isoxaben Label Table

Summary of Labeling Changes for Isoxaben

Description Amended Labeling Language for Isoxaben Products Placement on Label

Products Labeled for Agricultural Use

HERBICIDE RESISTANCE MANAGEMENT

Herbicide Mode of 

Action 

“Group 21 HERBICIDE” Front Panel, upper right 

quadrant, surrounded by a 

black (or suitable color) 

rectangle

Weed Resistance 

Management

“Weed Resistance Management:”

 Instructions to alternate use of products containing 

isoxaben with other herbicides with different 

mechanisms of action;

 Recommendations to scout for weeds before 

isoxaben application for identification and growth 

stage and after isoxaben application to look for poor 

performance or likely resistance; 

 Instructions to clean application equipment between 

sites and to avoid moving plant material between 

sites; and 

 Instructions to report herbicide failure to local 

extension specialists, certified crop advisors, and/or 

isoxaben registrants. 

Directions for Use, prior to 

directions for specific crops 

under the heading” WEED 

RESISTANCE 

MANAGEMENT” 

Best Management 

Practices

Best Management Practices:

Proactively implementing diversified weed control strategies 

to minimize selection for weed populations resistant to one or 

more herbicides is recommended. A diversified weed 

management program may include the use of multiple 

herbicides with different modes of action and overlapping 

weed spectrum with or without tillage operations and/or other 

cultural practices. Research has demonstrated that using the 

labeled rate and directions for use is important to delay the 

selection for resistant weeds. Scouting after herbicide 

application is important because it can facilitate the early 

identification of weed shifts and/or weed resistance and thus 

provide direction on future weed management practices. One 

of the best ways to contain resistant weed populations is to 

implement measures to avoid allowing weeds to reproduce by 

seed or to proliferate vegetatively. Cleaning equipment 

between sites and avoiding movement of plant material 

between sites will greatly aid in reducing the spread of 

resistant weed seed.

Directions for Use, prior to 

directions for specific crops 

under the heading “BEST 

MANAGEMENT 

PRACTICES” 

ENVIRONMENTAL HAZARDS

General Labelling 

Statement is Consistent 

Across All Residential 

Use Products

Liquid Concentrate - Do not allow pesticide to enter or run 

off into storm drains, drainage ditches, gutters or surface 

waters. Applying this product in calm weather when rain is 

not predicted for the next 24 hours will help to ensure that 

wind or rain does not blow or wash pesticide off the 

treatment area. Rinsing application equipment over the 

treated area will help avoid run off to water bodies or 

drainage systems.

Environmental Hazards section
20

Summary of Labeling Changes for Isoxaben

Description Amended Labeling Language for Isoxaben Products Placement on Label

Broadcast Granular - Do not allow pesticide to enter or run 

off into storm drains, drainage ditches, gutters or surface 

waters. Applying this product in calm weather when rain is 

not predicted for the next 24 hours will help to ensure that 

wind or rain does not blow or wash pesticide off the 

treatment area. Sweeping any product that lands on a 

driveway, sidewalk, or street, back onto the treated area of 

the lawn or garden will help to prevent run off to water 

bodies or drainage systems. 

Dust - Do not allow pesticide to enter or run off into storm 

drains, drainage ditches, gutters or surface waters. Applying 

this product in calm weather when rain is not predicted for 

the next 24 hours will help to ensure that wind or rain does 

not blow or wash pesticide off the treatment area. 

Liquid Ready-to-Use (RTU) - Do not allow pesticide to enter 

or run off into storm drains, drainage ditches, gutters or 

surface waters. Applying this product in calm weather when 

rain is not predicted for the next 24 hours will help to ensure 

that wind or rain does not blow or wash pesticide off the 

treatment area. 

Ground Water 

Advisory

Ground Water Advisory: This pesticide has properties and 

characteristics associated with chemicals detected in ground 

water. This chemical may leach into ground water if used in 

areas where soils are permeable, particularly where the water 

table is shallow.

Environmental Hazards section

Surface Water 

Advisory

This pesticide may impact surface water quality due to runoff 

of rain water. This is especially true for poorly draining soil 

and soils with shallow ground water. This product is 

classified as having a high potential for reaching surface 

water via runoff for several months or more after 

application. A level, well-maintained vegetative buffer strip 

between areas to which this product is applied and surface 

water features such as ponds, streams, and springs will reduce 

the potential loading of isoxaben from runoff water and 

sediment.

Environmental Hazards section

USE RESTRICTIONS

Consistent Application 

of NY State 

Restrictions

Not for sale, distribution or use in New York State. Use Restrictions section

Consistently Prohibit 

Aerial Uses

Do not apply by air. Use Restrictions section

USE PRECAUTIONS

For Labels with Turf 

Use Patterns, 

consistently establish 

Restrictions on Use in 

Turfgrass Grown for 

Seed

Do not apply <PRODUCT NAME> to turfgrass grown for 

seed.

Use Precautions section

SPRAY DRIFT MANAGEMENT

Spray drift language Spray equipment and weather affect spray drift. Consider all 

factors when making application decisions. Where states 

have more stringent regulations, they must be 

Directions for Use, prior to 

directions for specific crops 
21

Summary of Labeling Changes for Isoxaben

Description Amended Labeling Language for Isoxaben Products Placement on Label

observed. Avoiding spray drift is the responsibility of the 

applicator or grower. To reduce the potential for drift, the 

application equipment must be set to apply medium to coarse 

droplets (i.e., ASAE Standard 572) with corresponding spray 

pressure. Use high flow rate nozzles to apply the highest 

practical spray volume. With most nozzle types, narrower 

spray angles produce larger droplets. Follow the nozzle 

manufacturer's directions on pressure, orientation, spray 

volume, etc. in order to minimize drift and optimize coverage 

and control.

Wind: Avoid making applications when spray particles may 

be carried by air currents to areas where sensitive crops and 

non-target plants are growing. Do not spray near sensitive 

plants if wind is gusty, below 2 mph, or in excess of 10 mph 

and moving in the direction of adjacent areas of sensitive 

areas. Local terrain may influence wind patterns; the 

applicator must be familiar with local conditions and 

understand how they may impact spray drift.

Sensitive Areas: Sensitive areas to this product are defined 

as bodies of water (ponds, lakes, rivers, streams, and ditches), 

wetlands, habitats of endangered species, and non-labeled 

agricultural crop areas. Applicators must take all precautions 

necessary to keep spray drift from reaching those areas.

Temperature Inversion: A surface temperature inversion 

(i.e., increasing temperature with increasing altitude) greatly 

increases the potential for drift. Presence of ground fog is a 

good indicator of a surface temperature inversion. Do not 

apply during temperature inversions. Always make 

applications when there is some air movement to determine 

the direction and distance of possible spray drift.

Boom Height: Set the boom and make applications at the 

lowest height that safely permits uniform coverage of the soil 

and minimizes droplet evaporation. Boom or nozzle 

shielding can reduce the effects of wind or air currents on 

drift. Verify that the shields do not interfere with uniform 

deposition of product prior to application.

under the heading “SPRAY 

DRIFT MANAGEMENT”